(1) Field of the Invention
The present invention relates to a method of using iguratimod (N-[7-[(methanesulfonyl)amino]-4-oxo-6-phenoxy-4H-1-benzopyran-3-yl]formamide) or a salt thereof and an immunosuppressive agent in combination for the treatment such as the therapy or prevention of autoimmune diseases. The present invention also relates to a pharmaceutical composition containing iguratimod or a salt thereof and an immunosuppressive agent, which is useful in the treatment such as therapy or prevention of autoimmune diseases.
(2) Description of Related Art
Chronic arthritis caused by connective tissue diseases typified by autoimmune diseases such as rheumatoid arthritis brings about, for example, dysfunction due to the progression of cartilage and/or bone destruction, and largely affects daily life. Although the cause of such autoimmune diseases remains unclear, these diseases are considered to be triggered by excessive immune response to autoantigens.
Against this backdrop, disease-modifying anti-rheumatoid drugs (DMARDs) typified by immunomodulatory drugs (e.g., gold preparation, D-penicillamine, and salazosulfapyridine) and immunosuppressive agents (e.g., methotrexate and tacrolimus) are used as the first drug of choice in the medical therapy of rheumatoid arthritis and other types of arthritis or autoimmune diseases. Particularly, for the therapy of rheumatoid arthritis, use of DMARDs from an early stage after definitive diagnosis is recommended by treatment guidelines (Arthritis Rheum. Vol. 39, p. 713-722 (1996); and Arthritis Rheum. Vol. 46, p. 328-346 (2002)). Now, immunological therapy is absolutely important for this disease. In addition, steroidal anti-inflammatory drugs and nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin or indomethacin are used according to the symptoms of patients. These therapeutic methods currently used, however, cannot completely suppress the progression of joint or bone destruction, which is the biggest problem in arthritis, and long-term use thereof is difficult in terms of adverse reactions. Thus, these therapeutic methods have not yet provided as a satisfactory treatment.
Immunosuppressive agents are known to be effective for autoimmune diseases. These immunosuppressive agents inhibit antibody production, cytokine production, and lymphocyte or synovial cell proliferation, etc., thereby suppressing excessive autoimmune phenomena and, by extension, symptoms of arthritis or the like. Methotrexate, leflunomide, and tacrolimus are commercially available as immunosuppressive agents. Drug development is still continuing. Moreover, steroid drugs have strong immunosuppressive effects, as well known.
Iguratimod having anti-arthritic effects exhibits inhibitory effects on cytokine production and immunomodulatory effects (Chem. Pharm. Bull., Vol. 48, p. 131-139 (2000); J. Pharmacobio-Dyn., Vol. 15, p. 649-655 (1992); and Int. J. Immunotherapy, Vol. 9, p. 69-78 (1993)) and is useful in the therapy of rheumatoid arthritis and other types of arthritis or autoimmune diseases (Japanese Patent No. 3521145). Unfortunately, iguratimod is known to have adverse reactions such as hepatocellular damage (Mod. Rheumatol., Vol. 17, p. 1-9 (2007)).
A method using therapeutic drugs for arthritis in combination is known (N. Engl. J. Med., Vol. 334, p. 1287-1291 (1996)) and, however, does not produce satisfactory therapeutic effects due to the limited number of therapeutic drugs for arthritis. Also, such combined use is generally known to produce the additional or additive effect of improving arthritis symptoms. Reportedly, the combined use of iguratimod and methotrexate potentiates therapeutic effects on arthritis (Arthritis Research & Therapy), Vol. 10, No. 6, R136 (2008)).
However, it has been totally unknown so far that the combined use of therapeutic drugs for arthritis reduces the respective adverse reactions of the drugs.